Valuable derivatives of sulphonamides and a method of making the same



Patented Nov. 19, 1946 'VALUABLE DERIVATIVES OF SULPHON- AMIDES AND A METHOD OF MAKING THE SAME Max Dohrn, Berlin-Charlottenburg, and Paul Diedrich, Finkenkrug, Osthavelland, Germany, asslgnors to Schering Corporation, Bloomfield, N. J a corporation of New Jersey No Drawing. Application .Ianuary 31, 1939, Se-

rial No. 253,734.

9 Claims. 1

This invention relates to valuable derivatives of sulphonamides and a method of making the same.

As particularly valuable therapeutic agents in combating bacterial infections such as streptococcic, staphylococcic, pneumococcic, and septicemia conditions, have proved compounds of the type of the sulphonamides such as are described, for example, in German Pattents Nos. 607,537, 610,320,. 638,701, French Patents Nos. 812,053, 820,546, British Patents Nos. 482,576 and 462,765, Swiss Patents Nos. 192,699 and 192,700, U. S. Patents Nos. 2,111,768 and 2,111,913 and others; compare also the work of Fourneau, Trfouel, Nitti and Bovet, Comptes Rendus Soc. Biol. 1936, vol. 122, pages 258-259; Trfouel, Nitti and Bovet, Annales de lInstitut Pasteur, vol. 58, pages 30-47 (1937); Buttle, Gray and Stephenson, Lancet of 6.6.36, pages 1286- 1290; Mayer, Oechslin, Comptes Rendus, vol. 205, pages 181-182 (1937); Goissedet, Despois and Mayer, Comptes Rendus Soc. Biol. 1936, vol. 121, pages 1082-1084 and others. All these compounds contain a sulphonamide group SO2NH2 connected to an aromatic, heterocyclic or aromaticheterocyclic residue. Very active compounds of this class of substances contain in p-position to the sulphonamide group an amino group or a group convertible thereinto. As the best known compounds of this type may be mentioned the psulphanilic acid amide NH2.C6H4.SO2NH2 and the azodyestuffs derived therefrom of the type of 4-sulphonamido-2'.4'-diaminoazobenzene In compounds of this type also the nuclear bound amino groups can be substituted by suitable substituents, for example, by acylresidues, in particular by those containing acid groups, or by carboxy-alkyl residues, by carbohydrate residues, by benzyl residues and the like. A whole series of compounds of this type is diflicultly soluble or insoluble in water so that the administration thereof presents difliculty.

In accordance with the present invention particularly valuable derivatives of compounds of this type are produced when in them a hydrogen atom of the sulphonamide group is replaced by an acyl residue. The compounds thus obtained according to the invention correspond to the following formula:

In this formula R indicates an aromatic, heterocyclic or aromatic-heterocylic residue containing at least one nuclear bound amino group or a group In Germany February 2,

convertible thereinto, while X indicates an acyl residue of a carboxylic acid.

In accordance with the invention by the introduction of such an acyl residue into the sulphonamide group the hydrogen atom still present in the sulphonamide group becomes replaceable by metal. By replacement of this hydrogen atom by alkali metal it is possible to convert otherwise insoluble compounds of the above mentioned class of substances into compounds easily soluble in water with neutral reaction. By this means the possibility is provided of employing all the compounds according to the invention not only as such but in the form of their water-soluble salts in aqueous solution and to administer them, for example, by intravenous or subcutaneous injection whereby a more rapid effect is promoted. In addition there is the fact that the therapeutic activity of these substances is not reduced by the reaction specified but in many cases even increased.

Even if a few of the already known compounds of the sulphonamide type are capable of forming water-soluble salts as, for example, the paminobenzene-sulphonamide hydrochloride, the salts obtained according to the present invention are distinguished from these known salts by the fact that the latter do not pass into solution with neutral reaction and on this account can find no application for injection purposes.

For the manufacture of the compounds according to the present invention certain types of reaction may be followed which in themselves are known to the expert. Essentially two main groups of methods of production can, be distinguished, namely;

1. Such in which the residue R.SOzNH-I is previously formed and the acyl group introduced,

2. Such in which the residue -NH.X is previously formed and the residue R.SO2 introduced.

To the first mentioned group of methods of manufacture belongs the simplest method, namely the acylation methods known per se, for instance, by means of acid anhydrides, acyl chlorides, ketenes and the like. If the residue R of the above formula in addition contains an amino group, the acylation must naturally be carried 0: 1.; in such a manner that together with the acylation of the amino group the acylation of the sulphonamide group simultaneously takes place, that i to say in general an excess of acylating agent will be employed. 'If necessary then by partial hydrolysis the acyl group of the nuclear bound amino group may be split off again.

employed in which from the commencement only an acylation of the sulphonamide group takes place and the nuclear bound amino group remains unchanged, as, for example, by causing the acylating agent to react on the silver compound of the sulphonamide.

This group of manufacturing processes includes also all the processes in which such acylated sulphonamides are employed as starting materials in which the nuclear bound amino group is first produced after the production of the acylated sulphonamide group. It comprises therefore essentially two stage processes in which in fact sulphonamides which contain a group convertible into the amino group are first acylated whereupon the nuclear bound amino group is produced. The various methods for converting nitrogencontaining and non-nitrogen-containing groups into an amino group are Well known and are described, for example, in Houben Die Methoden der organischen Chemie, second edition, 1923- 1924, vol. 2, page 315 et seq., vol. 4, page 247 et seq., page 337 et seq., page 339, et seq., and page 354 et seq. As example may be mentioned the acylation of p-nitrobenzene-sulphonamide with subsequent reduction of the nitro group to the amino group. Instead of the nitro group also any other of the groups convertible into the amino group can be present, for example, the nitroso, azo, azoxy, hydrazo and the like groups which by reduction are converted into the amino group, halogen, which by treatment with ammonia, suitably in the presence of catalysts, gives the amino group; the acylamino and azo-methine groups, which can be hydrolysed to the amino group, or anacid amide or hydrazide group which can be converted into the amino group by Hofimann, Curtius or the like degradation reactions, and others. To this group of manufacturing processes belongs also the process in which the nuclear bound amino group before the acylation is converted into such an acylamino group as can more easily be split off to the amino group than is the case with the acylated sulphonamide group. Such groups are, for example, the carbomethoxy, the carbobenzyloxy group and others as are mentioned, for example, in German Patent 556,798. These can easily by reduction treatment or by hydrolysis be split off again without the acylated sulphonamide group being influenced. Also the method of benzylating the amine group can be used with advantage for this type of reaction.

To this group of manufacturing processes belong finally also the methods in which at first aromatic, heterocyclic or aromatic-heterocyclic amino-sulphonamide compounds are acylated in the sulphonamide group, and then the free or again liberated nuclear bound amino group is diazotized and the diazo compound obtained coupled in the manner known per se, corresponding, for example, to the directions of German Patents Nos. 607,537, 610,320 and others with aromatic, heterocyclic or aromatic-heterocyclic bases which are capable of coupling. There are obtained in this manner azo compounds acylated in the sulphonamide group which on the one hand contain a nuclearboun-d amino group and on the other an acylated sulphonamide group and which likewise constitute valuable therapeutic agents. Obviously there can be employed for the manufacture of such azo compounds also other manufacturing methods known per se as are mentioned in the above specified patents. Thus, for example, an aromatic, heterocyclic or aromatic-heterocyclic nitro compound which contains a nuclear bound basic nitrogen atom can be condensed in customary manner to the azo compound. It is also possible to reduce corresponding azoxy compounds to the azo compounds or to dehydrogenate correspondingly constituted hydrazo-compounds to the azo compounds.

The formation of the nuclear-bound amino group by splitting of substituents or by conversion of another group convertible thereinto (nitro-, azo-, halogenand similar groups) is necessary in certain instances to render the compound therapeutically active. Thus, such conversion is necessary in the base of the p-halogeno-sulfonacylamides, suchas p-chloror pbrombenzenesulfonacetamide, since such compounds, as tests have shown, are inactive, and active compounds are produced therefrom only by conversion into the corresponding p-aminobenzenesulfonacylamides.

To the second group of manufacturing processes belong all the processes in which such sulphonic'acids or their derivatives as contain a nuclear bound amino group or a group convertible thereinto, primarily their halides. in particular the sulphochlorides, are brought into reaction in the customary manner with the corresponding acid amides in the presence or absence of condensing agents and/or catalysts and, if necessary, the nuclear bound amino group produced. Instead of the acid amides it is also possible to employ, although less preferably, their metal acids or their salts with acid amides which contain a halogen attached to nitrogen.

Of course, also other known methods for making the compounds according to this invention as they are described, for instance, in the above mentioned patents or literature references may be employed. The essential feature of this invention consists, however, in the production of compounds of the general formula R.SO2.NH.X.

As particularly valuable starting materials for the reaction of the present invention have proved the following substances:

p-Aminobenzene-sulphonamide,

p-Benzylaminobenzene-sulphonamide,

p-Aminobenzene-sulphonamido-benzene-m sulphonamide, and

p-Amino benzene sulphonamido p sulphonamide and their acylamino derivatives or sulphochlorides, azo-dyestuffs of the type of the 4-sulphonamido-'2'.4-diamino-1.1-azobenzene, the glucosides of p-amino-benzene-sulphonamide and others as are described in the patents and literature references set forth above and in the pending patent applications Ser. No. 147,478 of June 10, 1937, and Ser. No. 210,746 of May 28, 1938.

By interaction of the compounds according to the invention acylated on the sulphonamide group, with metal oxides, hydroxides or carbonates or the like there are obtained the corresponding metal'compounds; Thus it is easy to manufacture the alkali compounds by treating the new compounds with the calculated quantity of alkali hydroxide solution or sodium carbonate to a neutral reaction and, if necessary, salting out th alkali salt or precipitating it by the addition of organic solvents miscible with water. 01'.

course, the salts can be isolated from their solutions by simply evaporating the latter to dryness.

It is also possible, however, to produce other metal compounds, such as the alkaline earth, gold, copper, mercury, silver, aluminum, magnesium and the like compounds which are likewise of practical importance. For the manufacture of these salts there is especially suitable the known method of double decomposition, according to which, for instance, the alkaline earth metal salts of the acylated sulphonamides (that is, of alkaline earth metals whose sulphates are insoluble) are reacted with soluble sulphates of heavy metals. Thereby the insoluble alkaline earth metal sulphate precipitates while the soluble heavy metal salt of the acylated sulphonamide remains in solution and is isolated therefrom. Also organic bases as, for example, alkylamines, alkanol amines such as ethanolamines, pyridine, aniline, 1 phenyl 2.3 dimethyl-4-dimethylamino-S-pyrazolone, quinine and others are suitable for salt formation.

Both the acylated sulphonamide compounds of the formula R.SOz.NH.X and also their metal and other derivatives are intended to find application not only as therapeutic agents but also as intermediate products for the manufacture of other pharmaceutical and. technically valuable substances, for example, for the manufacture of plant protecting agents and the like.

The following examples illustrate the invention without, however, limiting the same to them:

EXAMPLE 1 4-aminobeneene-sulphonacetyl-amide 17.2 grams of 4-aminobenzene-sulphonami de are heated to boiling with 75 cc. of acetic anhydride for one hour and thereupon the diacetyl product caused to separate by stirring into ice water. After recrystallisation from alcohol the 4- acetylaminobenzene-sulphonacetyl amide forms colorless prisms of melting point 253 C. with decomposition. The product is easily soluble in alkalies and forms neutral salts. The acetylation can also take place with acetyl chloride. Instead of the 4-aminobenzene-sulphonamide also 4- acetylaminobenzene-sulphonamide can be employed. The action of 4-acetylaminobenzenesulphonic acid chloride on acetamide yields the same product.

By heating the diacetyl compound with sodium hydroxide solution partial saponification of the acetyl groups takes place. 25.6 grams of diacetyl compound are heated to boiling for some hours with 100 cc. of 2 N sodium hydroxide solution. The precipitate produced by acidification of the solution with acetic acid is filtered off and treated with dilute sodium carbonate solution. The 4-aminobenzene-sulphonacetylamide passes into solution while the simultaneously formed 4- acetylaminobenzene=sulphonamide remains undissolved. It is filtered with suction and the filtrate again acidified with acetic acid. The 4- aminobenzene-sulphonacetamide separates out and is recrystallised from water. It forms colorless lustrous rhombic crystals of M. P. 181 C. It is easily soluble in alcohol and acetone, more t6 1 diflicultly in water, insoluble in benzene and chloroform.

' 'Exurru: 2

4-propionylaminobenzene-sulphon-propidnylamide 17.2 grams of 4-aminobenzene-sulphonamide are heated to boiling for one hour with 20 cc. of propionic acid anhydride. The working up according to example 1 yields the dipropionylaminobenzene sulphonamide. Recrystallised from alcohol it forms colorless microscopic needles of M. P. 232 C. The product is soluble in sodium carbonate solution and can be partially saponifled by heating with sodium hydroxide solution as in Example 1, yielding 4-aminobenzene-sulphon-propionyl-amide of M. P. 131 C.

EXAMPLE 3 4-acetylaminobenzene-sulphonbenzoylamide benzene-sulphonbenzoyl-amide obtained has the melting point of 179-186" C.

EXAMPLE 4 4-benzylaminobenzene-sulphonacetamide 26.2 grams of 4-benzylaminobenzene-sulphonamide are heated for some hours with 250 cc. of acetic anhydride. The working up according to Example 1 yields the 4-benzylaminobenzenesulphonacetylamide. It is purified by recrystallisation from alcohol and then forms microscopic needles of melting point of 143-144 C.

EXAMPLE 5 4.4- acetylaminobenzene-sulphonamidobenzenesulphonacetylamide 32.7 grams of 4.4-aminobenzene-sulphonamidobenzene-sulphonamide are heated to boiling with 200 cc. of acetic anhydride. After solution has taken place the whole is boiled for a further hour and then the diacetyl compound caused to separate by pouring the solution into ice water. -The precipitate is purified by dissolving in sodium carbonate solution and precipitation of the filtrate with acetic acid. Recrystallised from dilute alcohol the product forms colorless needles which melt at 178 C. By partial saponification with normal sodium hydroxide solution the corresponding amino product of M. P. 187 C. is obtained.

EXAMPLE 6 4-acetylaminobenzene-sulphonamido-3'- benzene-sulph0nacet11lamide 32.7 grams of 4-aminobenzene-sulphonamido- B-benzene-sulphonamide of M. P. 156 C. (produced by the action of 4-acetylaminobenzenesulphonic acid chloride on 3-aminobenzene-sulphonamide and subsequent saponification of the acetyl group of the condensation product) are heated with 200 cc. of acetic anhydride for one hour to boiling and thereupon the diacetyl product isolated as described in Example 5. After recrystallisation from dilute alcohol the product melts at 145-146. By partial saponification the corresponding amino compound is obtained.

EXAMPLE 7 4-acetylsulphonamidobenzene-2'.4'-diamino-1.1'-

- azobenzene 21.4 grams of 4-aminobenzene-sulphonacetamide are diazotised in hydrochloric acid solution with 6.9 grams of sodium nitrite and the cold diazonium chloride solution treated with a hydrochloric acid solution of 11 grams of m-phenylenediamine. The coupling product immediately separates as a dark red precipitate. It is filtered with suction, taken up with dilute sodium carbonate solution, filtered and acidified in the hot with acetic acid. The dyestufi separates in the form of blue-red leaflets of metallic lustre. On heating decomposition takes place at 180 C.

The same product is obtained when the 4- sulphonamido 2'.4'- diamino-l.1-azobenzene is acetylated and partially saponified. The dyestufl is easily soluble in dilute sodium, carbonate solution.

Exmrta 8 4-aminobenzene-sulphonacetylamide times the quantity of acetic anhydride and pouring or the solution into water the-acetyl derivative is precipitated. It is filtered with suction, taken up in dilute sodium carbonate solution. filtered from any unchanged tarting material and in the filtrate precipitated again by hydrochloric acid.

The --4-N-carbonic acid benzyl ester aminobenzene-sulphonacetylamide melts after recrystallisation'from methyl alcohol at 167-168 C. The

yield amounts to 200 grams. r

To split off the carbobenzyloxy group, 200 grams of the 4-N-carbonic acid benzyl ester aminobenzene-sulphonacetylamide are dissolved in 3 litres of alcohol and with the addition oi. 5 grams of'palladium black shaken with hydrogen so long as the latter is still taken up. 'For this purpose 7.6 litres of hydrogen are employed.

The solution is filtered oil from catalyst, concen-- trated and the residue recrystallised from water. The yield amounts to 106 grams of 4-aminobenzene-sulphonacetylamide of melting point of 181 C. The same ld is obtained when the catalytic hydrogenat'on is carried out in aqueous alkaline instead of in alcoholic solution.

The splitting off of the benzyl-carbonic acid residue can also take place by several hours treatment with three times the molar quantity of normal sodium hydroxide solution. at 60 C.

, Exmrnn 9 40 grams oi. carbanilic acid ethyl ester (Hente schel, Berichte vol. 18, page 978) are, introduced at 0 C. into 160 grams of chlorsulphonic acid.

The mixture is heated for an. hour to 55-60 C.

- ing for 2 hours. The acetylated product is introduced into water, filtered with suction and reprecipitated. It melts .after recrystallization irom dilute acetone at 244 C.

For splitting ofl. the carbethoxy group the 4 carbethoxy amino benzene sulphonacetylamide is dissolved in seven times the quantity oil 2 N sodium hydroxide solution and the solution heated for 10 minutes to 80 C. By acidification with acetic acid the 4-aminobenzene-sulphonacetylamide is precipitated and is purified by recrystallisation from water. Melting point 181 C. The yields according to this process correspond to those given imijxample 8.

Instead of 4-carbethoxy-aminobenzene-sulphonamide there can also be employed as starting material the carbomethoxy compound; it is obtained in the following manner:

82.3 grams of the sodium salt or carbomethoxy-sulphanilic acid (Niilting, Berichte 21, 3155) are ground with 70 grams oi! phosphorus pentachloride. The solid mass is introduced into ice water, the undissolved portions filtered with suction and washed iree from acid. The amide is obtained by introduction of ammonia'into the ethereal solution of the sulphochloride (melting point 117-118 C.) The carbomethoxy-sulphanilic acid amide melts at 226-227" C.

EXAMPLE 10 4-aminobenzene-sulphonacetamide-glucoside 21.4 grams of 4-aminobenzene-sulphonacetamide are heated to boiling with 17.1 grams of glucose and 200 cos. of absolute ethyl alcohol until a clear solution is produced. From the solution on long standing the glucose compound ciystallises in colorless needles. The crystals are separated and recrystallised from absolute ethyl alcohol. The melting point is 191 C. The compound is easily soluble in water, more dimcultly in ethyl alcohol. The alkali salts are easily soluble in water with neutral reaction.

I EXAMPLE 11 4.4-disulphonacetamide-diphenyl-urea Into a solution of 21.4 grams of 4-amino-benzene-sulphonacetamide in 200 cc. of 2 N sodium hydroxide solution is introduced at 50 C. a strong stream of phosgene. When the reaction is complete the precipitate produced is filtered with suction and for purification precipitated from an alkaline solution in the hot with acetic acid. The product forms colorless microscopic needles which decompose at 255 C. The yield is quantitative. The product is very difilcultly soluble in organic solvents. The water-solubility of its alkali salts is considerable.

EXAMPLE 12 4 -aminobenzene-sulphon-nicotoylamide 24.4 grams of 4-carbethoxy-sulphanilic acid amide are dissolved in 250 cc. 0! pyridine and with stirring and cooling 14.2 grams of nicotinic acid chloride introduced drop by drop. The clear solution is introduced into ice water and treated with hydrochloric acid to an acid reaction to Congo red. The precipitate is isolated and recrystallised irom dilute alcohol. The product forms needles of M. P. 241 C.

For saponification of the carbethoxy group 30 grams of 4-carbethoxyaminobenzene-sulphonnicotoylamide are allowed to stand for 24 hours in 210 cc. of 2 N sodium hydroxide solution. The solution is then acidified with acetic acid, the precipitate filtered with suction washed with water and recrystallised from dilute alcohol. The 4 aminobenzene sulphon nicotoylamide forms colorless needles and melts at 246 C.

EXAMPLE 13 4-aminobenzene-salphonbatyryl-amide 4-aminobenzene-sulphoncrotonyl-amide 24.5 grams of .4-carbethoXy-sulphanilio acid amide are heated for 2 hours to 145 C. with 125 grams of crotonic acid and 11 grams of crotonic acid chloride. After cooling the reaction mixture is stirred into 2 liters of water. The undissolved portion is separated, taken up in sodium carbonate solution and precipitated after filtration with acetic acid. The crotonylic derivative redissolved from alcohol melts at 224 C.

Saponification yields the 4-aminobenzenesulphoncrotonyl-amide which on recrystallisation from water melts at 175 C.

EXAMPLE 15 4-acetylaminobenzene-suZphon-pmitmbenzoylamide 21.4 grams of 4-acetylaminobenzene-sulphonamide are dissolved in 200 cc. N sodium hydroxide solution and are shaken with 18.6 grams of 4-nitrobenzoy1 chloride for several hours. The filtered solution is acidified, the precipitate is dissolved in sodium carbonate solution, again filtered, and the filtrate precipitated by means of acid. On recrystallisation from alcohol the 4-acetylaminobenzene-sulphon-p nitrobenzoylamide of M. P. 256 C. is obtained.

EXAMPLE 16 4-benzyZaminobenzene-sulphon-acetyl-amide 21.4 grams of 4-aminobenzene-sulphon-acetylamide obtained, for instance, according to EX- ample 1 and having a melting point of 181 C. are heated with 12.6 grams of benzylchloride, 24 grams of calcium carbonate, and 500 cc. of water for several hours while stirring, to boiling. After adding 6 grams of sodium carbonate the mixture is again heated to boiling, filtered while hot,

hydroxide solution.

10 and the filtrate is precipitated with hydrochloric acid. The precipitate consists of 4-benzylaminobenzene-sulphonacetamide which 'on recrystallisation from alcohol melts at 143-144 C. The yield amounts to 15 grams.

EXAMPLE 17 4-acetylsulphamidophenyl-azo-I (naphthal- 6'.8'-disulphonic acid) 21.4 grams of 4-aminobenzene-su1phon-acetylamide obtained, for instance, according to Example 1 are diazotized and in sodium carbonate solution coupled with a solution of 35 grams of 2-naphthol-6.8-disulphonic acid sodium salt. In order to isolate the reaction product the solution is slightly acidified and the dyestuff is salted out by addition of sodium chloride. The disodium salt obtained thereby is recrystallised from dilute alcohol and forms vermillion-reddish col ored prismatic needles which decompose on heating at 333C.

EXAMPLE 18 4-aminobenzene-sulphonpropionyl-amid 24.5 grams of 4-carbethoxy-aminobenzenesulphon-amide are heated with cc. of propionic acid anhydride for one hour to boiling. On stirring the mass into ice-water an oil precipitates that soon solidifies. After recrystallisation the 4-carbethoxy-aminobenzene-sulphonpropionyl-amide is obtained in the form of needles having a melting point of 208 C. The yield amounts to 24 grams.

The saponification of the carbethoxy residue is carried out in the same manner as described in Example 9, i. e. by heating with 2 N sodium The 4-aminobenzene-sulphonpropionyl-amide obtained therefrom by acidifying with acetic acid solidifies after a short time and forms crystals that on recrystallisation from dilute alcohol melt at 130-131 C.

EXAMPLE 19 4-aminobenzene-sulphon-phenacetyl-amide 24.4 grams of 4-carbethoXy-sulphanilic acid amide are heated with 16 grams of phenacetyl chloride for several hours to -170 C. The cooled reaction mixture is dissolved in dilute sodium carbonate solution and is acidified after filtration, with hydrochloric acid. The 4-carbethoxy-sulphanilic acid phenacetyl amide pre cipitated thereby is recrystallised from alcohol and melts at 209 C.

The saponification of this compound is carried out by treating the same with 2 N sodium hydroXide solution. The 4-aminobenzene-sulphonphenacetyl-amide obtained thereby melts after recrystallisation'from dilute alcohol at 182 C.

EXAMPLE 2O 4-carbethomy-aminobenzene-sulphonaminoacetic acid amide 24.4 grams of 4-carbethoxy-sulphanilic acid amide and 50 grams of chloro acetic acid anhydride are heated for one hour to 120-125 C. The reaction mixture is then triturated with water, the undissolved is removed by filtration, and is recrystallised from dilute alcohol. It melts at 229 C. The 4-carbethoxy-aminobenzene-sulphon-chloro-acetic acid amide yields on treatment with concentrated ammonia solution at ordinary room temperature 4-carbethoxy-aminobenzene-sulphonamino-acetic acid amide which on recrystallisation from water melts at 223 C.

, 11 Exmem 21 4- aminobenzene-sulphonsalicyltc acid amide 24.4 grams of 4-carbethoxy-sulphanilic acid amide and 15.7 grams of salicylic acid chloride are heated for several hours to 170-180 C. The reaction mixture is then dissolved in dilute sodium carbonate solution. The solution is filtered and precipitated with hydrochloric acid. By recrystallisation from glacial acetic acid the reaction product is obtained in a pure state and melting at 242 C. The saponification with 2 N sodium hydroxide solution yields 4-aminobenzene-sulphonsalicylic acid amide which on recrystallisation from water melts at 200-201 C.

EXAMPLE 22 I 4-aminobenzene-sulphonfuroyl amide 48.8 grams of 4-carbethoxy-sulphanilic acid amide are dissolved in 250 cc. of pyridine and -mixed while cooling and stirring, slowly and gradually with 26.5 grams of pyromucic acid chloride. After standing for some time the solution is poured into ice-water, filtered and the condensation product precipitated by acidifying with hydrochloric acid. The product purified by reprecipitation, melts at 259 C., with decomposition. The yield is almost quantitative. By treating this product with 2 N sodium hydroxide solution the carbethoxy group is split off and the 4-aminobenzene-sulphonfuroyl-amide is obtained on acidification. It forms a crystalline mass that on recrystallisation from water melts at 188- ExAmLn 23 4-aminobenzene-sulphon-hydnochaulic-acid amide 24.4 grams of 4-carbethoxy-sulphanilic acid amide are slowly heated with 29.6 grams of hydnochaulic (chaulmoogric) acid chloride (Wagner- Jauregg und Voigt, Berichte der Deutschen Chemischen Gesellschaft, vol. 71, page 1975) to 148 C. The reaction product is poured into water and is brought into solution with an amount of sodium carbonate suflicient to dissolve the product. After filtration hydrochloric acid is added and the precipitate is recrystallised from dilute alcohol in the presence of charcoal. The product forms colorless globular crystals having a melting point of 131 C.

EXAMPLE 24 4.4-diaminodiphenyl-disulphonadipic acid diamide EXAMPLE 25 4.4-diamin-diphenyl-disulphon-mucic acid diamide 48.8 grams of 4-carbethoxy-sulphaniiie acid amide are mixed with 24.7 grams of music acid ExAmPLz 26 4-aminobenzene-sulphoncarbethowy-amide 24.4 grams of 4-carbethoxy-sulphanilic acid amide are dissolved in 250 cc. of pyridine. To this solution there are added drop by drop while stirring 11 grams of chloro carbonic acid ethyl ester. The solution is. heated for several hours to -'70 C., then diluted with 5 times its amount of water and acidified with hydrochloric acid. The precipitate obtained is dissolved in dilute sodium carbonate solution in order to remove any non-reacted starting material, the solution is filtered, and the 4-carbethoxy-aminobenzene-sulphon-carbethoxy-amide is precipitated from the filtrate by means of hydrochloric acid. On recrystallisation from alcohol needles having a melting point of 162 C. are obtained.

By treating this product with 2 N sodium hydroxide solution the carbethoxy group is split 01! from the nuclear amido group. The 4-aminobenzene-sulphoncarbethoxy-amide obtained thereby melts after recrystallisation from alcohol at 133 C. It forms alkali salts that are readily soluble in water with neutral reaction.

Instead of reacting 4-carbethoxy-sulphanllic acid amide withone mol chloro carbonic acid ester one may proceed in such a manner that one mol of sulphanilic acid amide is reacted with 2 mols of chloro carbonic acid ester, thereby yielding the same dicarbethoxy-sulphanilic acid amide. I

- EXAMPLE 27 4-carbethoxy-aminobenzene-sulphon-carbethomlamide 26.4 grams of 4-carbethoxy-sulphanilic acid chloride are heated with grams of urethane to -150 C. until a sample is readily and completely soluble in dilute sodium carbonate solution. The reaction mixture is then dissolved in very dilute sodium carbonate solution, filtered. and the, filtrate acidified with acetic acid. The precipitate is recrystallised from alcohol and corresponds with the product obtained according to the preceding example.

EXAMPLE 28 I Salts of 4-aminobenzene-sulphon-acetamide (a) Sodium salt: 21.4 grams of 4-aminobenzene-sulphon-acetamideare dissolved in 100 cc. of N sodium hydroxide solution and the sodium salt is precipitated with alcohol after concentrating the solution. On recrystallisation from dilute alcohol the salt melts at 257 C.

(b) Barium salt: 21.4 grams of 4-aminobenzene-sulphon-acetamide are dissolved in an aqueous solution of 15.8 grams of barium hydroxide, the solution is evaporated to dryness and theresidue is recrystallised from dilute alcohol. Melting point: C. (with decomposition).

(c) Copper salt: The aqueous solution of 5 grams of the barium salt of 4-aminobenzene-sul- 13 phon-acetamide is mixed with 2.2 grams of copper sulphate. The flltrated solution is evaporated to dryness. A greenish powder is obtained.

(d) Ammonium salt: 4-aminobenzene-rsulphon-acetamide is dissolved in aqueous ammonia solution to neutral reaction and evaporated to dryness, A crystalline powder is obtained which on recrystallisation from alcohol melts at 156 C. with decomposition.

(e) Pyridine salt: 4-aminobenzene-sulphonacetamide is dissolved while heating in pyridine. The pyridine salt precipitated on cooling is recrystallised from alcohol. It has a melting point of 120 C.

(f) Diethanol amine salt: 21.4 grams of 4-aminobenzene-sulphon-acetamide are brought into solution by means of 10.5 grams of diethanolamine in 100 cc. of water. The residue obtained on evaporating the solution to dryness is recrystallised from dilute alcohol. Melting point of the salt: 155 C. (not sharp).

(9) Calcium salt: 21.4 grams of 4-aminobenzene-sulphon-acetamide are dissolved in 100 cc. of water while heating. To this solution there are added 5.0 g. of calcium carbonate. After boiling for a short time it is filtered and the illtrate evaporated to dryness. The residue is recrystallised from dilute alcohol.

(h) Silver salt: The aqueous solution 'of 4-aminobenzene-sulphon-acetamide sodium is mixed with a silver nitrate solution. The silver salt precipitates, is filtered off by suction, and is washed with water, alcohol, and ether. The product has a melting point of 216 C.

(i) Mercury salt: From an aqueous solution of the sodium salt of 4-aminobenzene-sulphon-acetamide the mercury salt of this sulphon amide compound is obtained by precipitation by means of a mercury acetate solution. It has a melting point of 251 C. (under decomposition).

(k) Quinine salt: 31.4 grams of 4-aminobenzene-sulphon-acetamide and 32.4 grams of quinine are dissolved in 200 cc. of alcohol. After distilling off the alcohol the quinine salt remains. It is soluble in water and melts at about 73 C.

(l) Morphine salt: 21.4 grams of 4-aminobenzene-sulphon-acetamide and 30.3 grams of morphine are dissolved while heating in 200 cc. of alcohol. The salt is precipitated by adding ether and has a melting point of 160 C. (not sharp).

EXAMPLE 29 4-aminobenzene-sulphonpropionul-amide calcium salt 22.8 grams of 4-aminobenzene-sulphonpropionyl amide are dissolved while heating in 150 cc. of water. To this solution 5.0 grams of calcium carbonate are added. After heating to boiling the solution is filtered and the filtrate is evaporated to dryness. The residue is recrystallised from dilute alcohol and has a melting point of 283 C. (with decomposition).

4-aminobenzene-sulphonfuroyl-amide magnesium salt 26.6 grams of 4-aminobenzene-sulphonfuroylamide are dissolved while heating in 200 cc. of water. The solution is heated to boiling with 4.2 grams of magnesium carbonate. The filtered so-. lution is concentrated by evaporation and is recrystallised from dilute alcohol.

14 Exams 31 4-aminobenzene-sulphonnicotoul amidesodium salt 27.7 grams of 4-aminobenzene-sulphon-nicotoyl-amide are dissolved in cc. of N sodium hydroxide solution. The solution is evaporated to dryness. The residue is recrystallised from dilute alcohol and gives a product that on heating decomposes beginning at 270 C. whereby coloration takes place.

Exlunmr: s2

4-aminobenzene-salphon-acetamide-alucoside-magnesium salt 37.6 grams of 4-aminobenzene-sulphon-acetamide glucoside are dissolved in cc. of water and boiled with 4.2 grams of magnesium carbonate. After evaporated to dryness the filtered solution, the residue is recrystallised from dilute alcohol and yields a'salt melting at about 167" C. 0

Exam ne 33 4.4'- aminobenzene sulphon amidobenzene sulphon-acetamide sodium salt 36.9 grams of 4.4'-aminobenzene-sulphonamidobenzene-sulphon-acetamide are dissolved in 100 cc. of water and 100 cc. of N- sodium hydroxide solution. From the concentrated solution alcohol precipitates the sodium salt in crystalline form.

- 1 EXAMPLE 34 4-benzylammobenzene-sulphon-acetamide calcium salt Examine 35' 4-acety'l-sulphamido-2'.4'-dia1nido-1 .1 -azobenzene-sodium salt 33.3 grams of 4-acetyl-sulphamido-2'.4'-diamldo-1.1-azobenzene are dissolved in 200 cc. of water and 100 cc. of N sodium hydroxide solution while heating. On addition of alcohol and ether the sodium salt crystallises from the solution in orange-brown needles of melting point of 207 C. (thereby decomposing).

EXAMPLE 36 2-aminopyridine-5-sulfonacetamide 10 grams of 2-aminopyridine-5-sulfonamide obtained from 2-chloropyridine-5-sulfonamide by reaction with concentrated aqueous ammonia solution at 150 C. in a closed container under pressure, are heated with 100 cc. of acetic acid anhydride for 1 hour to boiling; after cooling the solution is poured into about 1 liter of water while stirring, the precipitate obtained filtered of! by suction and recrystallized from water while adding animal charcoal. The 2-acetyl-aminopyridine-5-sulfonacetamide (melting point 278-79 C.) is soluble in sodium carbonate solution and insoluble in acids. It can be transformed by partial saponification into the 2-aminopyridine-5- sulfonacetamide.

In the same manner there is obtained on acetylatlon of 2-anilidopyridine-5-sulionamide or 15 melting point 178 0., produced from z-chloropyridine--sulfonamide by boiling with aniline, the 2-anilldo-pyridine-5-sulfonacetamide.

Exaurm 3'7 4-acetylsuljamidobenzene-Li aze-226- diaminomlridine forms orange-reddish needles of melting point 191-192? C. and is soluble in sodium carbonate solution.

Instead of pyridine compounds other heterocyclic compounds may be used likewise such as those of the quinoline, pyrrol, indol, pyrazol and the like series.

Instead of the acylating agents employed in these examples obviously also others can be employed, for example, the anhydrides or halides of higher fatty acids such as those of palmitic acid, hydnocarpus acid, phenyl-cinchoninic acid, Pyridine carboxylic acids and others.

It is true that sulphonamides amino substituted in the nucleus have previously been acylated, compare French'specification 820,546. As, however, is shown by the more detailed description of the specification in this case always 1 mol of acylating agent is employed for 1 mol of the sulphonamide. By this means, however, only the nuclear bound amino .group is acylated. According to the process of the present application,

however, an excess of acylating agent is employed wherein Y is a member of the group consisting of hydrogen and metals.

2. A process for preparing N'-acylsulfanilamides which comprises reacting sulfanilamide with at least two equivalents or a member of drolysing the N -acylamino group only of the resulting product.

8. N'-acylsulfanilamides of the following formula:

to the sulphur atom a ring carbon of an aromatic' residue which has an amino group linked through the nitrogen to a ring carbon in p-position to the first-mentioned carbon, to the action of at least 2 mols of an acylating agent to acylate both the amidic nitrogen and the nuclearly bound amino group, the sulfonamide group being converted into the group -SO2.NH.OC.R, the group OC.R being the acyl radical of a carboxylic acid.

7. In a process for the manufacture of N -acyl sulphonamides, the steps comprising subjecting a sulphonamide compound having directly attached to the sulphur atom a ring carbon of an aromatic residue which has an amino group linked through the nitrogen to a ring carbon in p-position to the first-mentioned carbon, to the action of at least 2 mols of an acylating agent to acylate both the amidic nitrogen and the nuclearly bound amino group, the sulfonamide group being converted into the group acid, and saponifying the 4-acylamino group to 4 yield the 4-aminobenzenesulphonacylamide.

9. In a process for the manufacture of N -acyl sulphonamides, the steps comprising subjecting a sulphonamide compound having directly attached to the sulphur atom a ring carbon of an aromatic residue which has an amino group linked through the nitrogen to a ring'carbon in p-position to the first-mentioned carbon, to the action of at least 2 mols of an acylating agent to acylate both the amidic nitrogen and the nuclearly bound amino group, the sulfonamide group being converted into the group the group -OC.R being the acyl radical of a carboxylic acid, and converting the N -acyl sulphonamides into salts by treatment with a memher" of the group consisting of organic and ino'ig'anic bases.

- MAX DOHRN.

PAUL DIEDRICH. 

